In this project, the intent is to understand the mechanism by which exposure to an environmental toxin causes disease-specific epigenetic changes. While epigenetic changes in response to toxicant and toxin exposure have been studied, the majority of these studies have examined changes in DNA methylation, which is thought to be a later more permanent epigenetic change. During tumorigenesis, which has been linked to toxin exposure, aberrant DNA hypermethylation silences the expression of tumor suppressor genes. Specifically understanding the initiation, timing, and molecular progression of epigenetic changes from acute exposure to disease formation will allow us to develop better prevention and treatment strategies for diseases caused by environmental exposure. We have demonstrated in vitro that exposure to oxidative damage causes acute genome-wide changes in the chromatin binding of epigenetic silencing proteins, suggesting a mechanism by which epigenetic changes may be initiated. Here we use exposure to toxigenic bacteria, enterotoxigenic Bacteroides fragilis (ETBF), which is known to be associated with acute and chronic colitis and colon cancer in humans, to induce colon inflammation followed by tumorigenesis in a mouse model. Therefore, understanding the mechanism behind epigenetic changes induced by these bacteria will be relevant to human disease. Furthermore, because like many toxicants and other toxins, exposure to ETBF causes an increase in inflammation and associated oxidative damage, the findings from our model can be translated to many different exposures that cause human disease. The goal of this application is to understand how toxin exposure initiates disease-specific epigenetic changes, including the timing and molecular progression of such changes. Using ETBF infection, we will determine if acute toxin exposure results in genome-wide changes in the chromatin binding of epigenetic silencing proteins and if this change in binding is dependent on oxidative DNA damage. Furthermore, using the ETBF model of inflammation-induced tumorigenesis we will investigate if these acute epigenetic changes result in disease-specific epigenetic changes as well as study the molecular progression from the enrichment of epigenetic silencing proteins at specific gene promoters to DNA methylation of those promoters.